Drug abuse and addiction are major burdens to society; economic costs alone are estimated to exceed half a trillion dollars annually in the United States, including health, crime-related costs, and losses in productivity. Genome-wide association (GWA) studies have identified a high number of common single nucleotide polymorphism (SNP) susceptibility alleles for a wide variety of common diseases. Of those, several have been performed for addiction phenotypes, i.e. smoking and nicotine dependence, alcohol dependence, polysubstance dependence and methamphetamine dependence/abuse. The most solid associations that have been discovered are between the CHRNA5/CHRNA3/CHRNB4, CHRNB3/CHRNA6 and CYP2A6/CYP2B6 regions and smoking behavior, nicotine dependence, and smoking-related diseases. While the success of recent GWA studies is impressive, the picture is clearly incomplete, and a substantial part of the heritability remains unaccounted for. We propose here to take advantage of the unique genetic resources gathered and developed at deCODE Genetics to lead the way into whole genome sequence-based human addiction genetics to uncover genetic high risk variants of moderate to rare frequency that affect the risk of addiction. To this end we focus on a well characterized population of over 15,000 that have been treated for addiction in Iceland. Whole genome sequencing using new massively parallel technologies is now feasible. Although costs are dropping rapidly, it is still very expensive to fully sequence the genomes of the thousands of individuals that are required for the next generation of well-powered disease association studies. Taking advantages of the large number of individuals genotyped using an Illumina SNP-chip, the extensive Icelandic genealogy, and recent methodological advances we have been able to systematically and reliably genome-wide phase the SNP genotypes for all the chip-typed individuals. Utilizing these results, and by sequencing the whole- genomes of 150 individuals from families with a high prevalence of amphetamine dependence we plan to perform whole-genome association studies of addiction with large effective sample sizes, studies that would otherwise be prohibitively costly. Our ability to phase the sequencing data together with the Icelandic genealogy also allows for detection of addiction variants with parental origin effect that are can otherwise be missed in standard association analysis. We expect to find many new associations, of novel types, that will increase our understanding of the genetics of addiction and drug abuse. The primary data will be made widely available for others to build on, and the resource will grow in value as the sequence is imputed into more people.